Prion diseases are fatal neurodegenerative diseases of humans and animals. The long-term goal of the proposed research is to define the pathway(s) and mechanism(s) involved in prion transmission. These events are central to understanding the pathogenesis of prion diseases, but the route(s) of horizontal transmission has not been adequately defined despite the importance of prion diseases to human, livestock, and free-ranging cervid health. Blocking the spread of the prion agent among hosts is one approach towards preventing these contagious diseases. Within an infected host, the dissemination of the prion agent to mucosal surfaces could result in prion agent shedding into bodily fluids. Since neurons replicate the prion agent to high levels, exposure of susceptible hosts to infectious sources derived from prion-infected neurons at the mucosa would likely contain the highest dose of infectivity and therefore, be the most effective at establishing a new prion infection. The specific hypothesis behind the proposed research is that the prion agent can be shed from olfactory neurons into nasal secretions and the amount of prion infectivity released will be enhanced under conditions that promote disruption of the olfactory epithelium. To test this concept the amount of prion infectivity shed into nasal lavages will be measured in the absence or presence of viral infection of the nasal cavity or after treatment with nasotoxic drugs. These studies can determine the role of olfactory neurons in prion shedding into nasal secretions and determine whether the ability of a common insult to the nasal epithelium to promote prion agent shedding could represent a novel mechanism to enhance prion transmission. PUBLIC HEALTH RELEVANCE: Prion diseases are fatal neurodegenerative diseases of humans and animals that can be transmitted vertically as well as horizontally through environmental contamination, ingestion of contaminated food, or by accidental exposure during medical procedures. These studies will investigate the role of prion agent shedding from olfactory neurons and the influence of common viral infections of the upper respiratory tract on enhanced prion shedding into nasal secretions. Identification of the route(s) of prion agent transmission is important in the development of therapeutic interventions that can prevent disease dissemination.